JPS61165365A - Novel production of beta-lactam compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound which is easily converted to an intermediate for synthesizing a 1-methylcarbapenem derivative having improved antimicrobial activity, by subjecting streoselectively a specific beta-lactam compound to hydrogenation reaction to a double bond. CONSTITUTION:A compound shown by the formula I (R is H, alkyl, or 1- hydroxyalkyl; R' is H, N atom-protecting group; R''1 is methyl, hydroxymethyl, alkoxycarbonyl, etc.; R' and R'' with neighboring N form 6-membered cyclic aminoacetal) is subjected to a catalytic hydrogenation reaction using a heterogeneous transition metallic catalyst, or reduction reaction with a metallic hydrogen complex compound in the presence of a transition metallic salt,or treated with hydroboration reagent, and treated with hydrogen peroxide in the presence of an alkali condition, to give the aimed compound shown by the formula II (R''2 is as shown for R''1 except methyl).

Description

[Detailed description of the invention] The present invention relates to a method for producing β-lactam compounds.

For more details, refer to the general formula (1) [wherein R represents a hydrogen atom or a lower alkyl group,
Alternatively, the hydroxyl group represents a protected or unprotected 1-hydroxy lower alkyl group. R' represents a hydrogen atom or a protecting group for a nitrogen atom, and R' represents a methyl group, a hydroxymethyl group, a hydroxymethyl group with a protected hydroxyl group,
A lower alkoxycarbonyl group or an aralkyloxycarzenyl group, or R' and R' represent an alkylene chain bonded to each other via an oxygen atom, and together with the adjacent nitrogen atom, a six-membered cyclic aminoacetal group. ] A β-lactam compound represented by the general formula [formerly [In the formula, R and R' have the same meanings as above, and R/%
represents a hydroxymethyl group, a hydroxymethyl group with a protected hydroxyl group, a lower alkoxycarzenyl group or an aralkyloxycarzenyl group, or R′ and R“
The symbol represents an alkylene chain bonded to each other via oxygen, and together with the adjacent nitrogen atom, represents a 6jk ring cyclic aminoacetal group. The present invention relates to a method for producing a β-2cutam compound represented by the following.

Chenamycin, which has useful activity as an antibacterial agent [US Pat. No. 3,950,357; J, Am.

Chem, Soc, , 100, ! 113 (
1978) ) from nature was reported, methods for obtaining various carbapenem compounds purely synthetically have been reported.

Recently, compounds in which the methylene group at the 1-position of the cicarpapenem skeleton has been substituted with various alkyl groups have been synthesized. In particular, 1-methylcarbapenem compounds have better in-vivo stability than conventional 1-position unsubstituted carbapenem compounds. It has been reported that it is excellent and extremely useful as an antibacterial agent. The synthesis method is reported in JP-A-58-26887 or Heterocycles, Vol. 21, p. 29 (1984), but it requires a long number of reaction steps and is complicated. In particular, a method for stereoselectively introducing a 1-methyl group has not yet been reported.

The present inventors conducted intensive studies on the stereoselective introduction method of 1-methyl group in the production of the above-mentioned 1-methylcarbapenem compound, and found that the double bond in the β-lactam compound represented by the general formula (1) It can be an excellent synthetic intermediate for the production of 1-methylcarbenem compounds by hydrogenation reaction to 1-methylcarbenem compound or by oxidation reaction with hydrogen peroxide after double bond hehyr-loboration. The present invention was completed based on the discovery that the β-lactam compound represented by the general formula CI) can be obtained stereoselectively.

The lower alkyl group represented by R in the general formula (1) includes methyl, ethyl, n-propyl, inpropyl,
Examples include linear or branched alkyl groups having 1 to 4 carbon atoms such as n-butyl and 5ec-butyl, and preferred examples include methyl and ethyl.

Further, as the alkyl group moiety of the 1-hydroxy lower alkyl group, the above-mentioned linear or branched alkyl groups having 1 to 4 carbon atoms can be mentioned, and suitable 1-hydroxy lower alkyl groups include hydroxymethyl, Mention may be made of 1-hydroxyethyl.

The protecting group for the nitrogen atom of R' may be any commonly used protecting group, but preferred are trialkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl, and substituted groups such as p-methoxyphenyl and 2,4-dimethoxyphenyl. Mono or diarylmethyl groups such as phenyl group, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, diphenylmethyl, di-p-ayucylmethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, etc. Examples include substituted methyl groups.

R//1 is, for example, a methyl group; a hydroxymethyl group protected with a general hydroxyl protecting group; a methoxyfluorinyl group, an ethoxycarmenyl group, an n-probyloxycarbonyl group, an improvised Lower alkoxycarzenyl groups such as biruoxycarbonyl group, n-butoxycargenyl group, t-butoxycarzenyl group; penciloxycarzenyl group, p-nitrobenzyloxy7
Examples include a carbonyl group, an aralkyloxycarmenyl group such as a 0-nitrobenzyloxycarmenyl group, a p-methoxypenzyloxycarmenyl group, and a diphenylmethyloxycarmenyl group.

Further, as R''=, examples similar to those for the above-mentioned R#! (however, excluding the methyl group) can be cited.

The protecting group for the hydroxyl group may be one that is commonly used, but preferably a lower alkoxycarmenyl group such as t-butyloxycarzenyl group; for example, a 2-iodinated ethyloxycarzenyl group, 2° 2.2-) Unahalogenoalkoxycarzenyl group such as lichloroethyloxycarl group; e.g. hahe/siloxycarzenyl group, 0-nitrobenzyloxcarbonyl group, p-nitrobenzyloxcarbonyl group, p - aralkyloxycarzenyl group such as methoxypenzyloxycardanyl group; e.g. trimethylsilyl group, t-butyldimethylsilyl group,
Trisubstituted 7 such as 1-butyldiphenylmethylsilyl group
Lyle group; Examples include substituted methyl groups such as methoxymethyl group, 2-methoxy7ethoxymethyl group, methylthiomethyl group, and nato-2hydropinyl group.

The manufacturing method of the present invention will be described in detail below.

As the hydrogenation reaction to the double bond according to the present invention, a general reduction reaction mode can be performed, and a divine reducing agent can be used. However, suitable methods include catalytic hydrogenation using catalysts, reduction using alkali metals such as lithium and sodium or their salts in liquid ammonia, reduction using diimines, metal hydrides (e.g. aluminum hydride, hydrogen Reduction reactions using metal hydride complexes (e.g. lithium aluminum hydride, sodium borohydride, etc.), etc. Preferred methods include heterogeneous reactions. Mention may be made of a catalytic hydrogenation reaction using a transition metal catalyst and a reduction reaction using a metal hydrogen complex in the presence of a transition metal salt (for example, sodium borohydride in the presence of cobalt chloride).

Catalytic reduction reactions in a hydrogen atmosphere are generally carried out in the presence of a catalyst.
Embodiments are possible in the hydrogenation reaction of carbon-carbon double bonds carried out in an inert solvent.

Examples of suitable catalysts from the standpoint of stereoselectivity include transition metal catalysts such as platinum oxide, platinum-activated carbon, palladium-activated carbon, and rhodium-activated carbon. Examples of inert solvents include methanol, ethanol, Examples include ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, cyclohexane, dimethylformamide, and further examples include mixed solvents of these organic solvents and water or phosphate buffer.

This reaction can be modified by selecting reaction conditions even when there are protecting groups for hydroxyl groups and nitrogen atoms that can be deprotected by catalytic hydrogenation. Particularly suitable catalysts that can selectively reduce only heavy bonds with good stereoselectivity include:
Examples include platinum oxide, platinum-activated carbon, etc.
Examples of the inert solvent include organic solvents such as acetonitrile, dimethylformamide, and ethyl acetate, and mixed solvents of these organic solvents and water. Further, in order to further enhance the selectivity, amines of Tanigata can be added. Suitable amines include, for example, tertiary amines such as triethylamine, tripropylamine, diisopropylethylamine, N,N-dimethylaniline, and particularly preferred ones include triethylamine and diisopropylethylamine. can.

It is desirable to use an amount of the catalyst and amines that is sufficient for the reaction to proceed sufficiently, but the amount of the catalyst is preferably 0.2 to 0.5 times the amount of the raw material compound (1).
It is preferable to use amines in an amount of 1.1 to 10 equivalents relative to the metal in the catalyst.

The reaction temperature can be suppressed or promoted by cooling or heating as appropriate, but the reaction temperature is preferably 0°C.
It can be carried out in a temperature range of 50°C. Further, the reaction may be carried out under pressure in order to promote the reaction, for example, the reaction may be carried out under a pressure ranging from normal pressure to 5 Kf/m''.

Next, the reduction reaction with a metal hydrogen complex compound is generally carried out in an inert solvent in the presence of a transition metal salt.

Although various embodiments of the selective reduction reaction of the carbon-carbon double bond of the β-unsaturated ester group are possible, suitable transition metal salts include salts of nickel, copper, cobalt, palladium, etc. The metal hydride complex compound is preferably sodium borohydride. Furthermore, suitable inert solvents include lower alcohols such as methanol, ethanol, and impropatol, tetrahydrofuran, water, and mixed solvents thereof.

It is desirable to use the transition metal salt and the metal hydrogen complex compound in an amount sufficient to allow the reaction to proceed sufficiently, but preferably the transition metal salt is used in an amount of 0.05 to 0.5 equivalent relative to the raw material compound (1). It is desirable to use 5 to 15 equivalents of the metal hydrogen complex compound. The reaction temperature can be suppressed or promoted by appropriately cooling or heating, but is preferably 0.
It can be applied at a temperature ranging from *°C to 50°C.

High P rosellation - Hydrogen peroxide oxidation reaction can be carried out in various ways that are generally carried out when converting olefins into alcohols. That is, this reaction is carried out in an inert solvent using a hydrovolelation reagent, followed by treatment with hydrogen peroxide under alkaline conditions.A suitable hydrolysis reagent is 9-melabisci'(3,3,1 )
Examples include nonane (9-BBN), thexylborane, and dicyclohexylgelane, and suitable inert solvents include ethers such as diethyl ether and tetrahydrofuran.

It is important to use the hydroborayone reagent and hydrogen peroxide in amounts that are sufficient for the reaction to proceed sufficiently.
Hydroboration is preferably performed at 0 to 50°C, and hydrogen peroxide oxidation is preferably performed at room temperature to 100°C.
It can be said to be ℃.

The stereoselectivity of the 5-position configuration of the β-2cutam compound represented by the general formula (1) obtained by the production method of the present invention changes depending on R', and in the hydrogenation reaction, the starting compound [l] When R' is a hydrogen atom, the [5S] coordination is preferentially obtained, and when / is a protecting group for the nitrogen atom, the [5R] coordination is preferentially obtained. It will be done.

On the other hand, in the hydrogelation-hydrogen peroxide oxidation reaction, R
Those with [5S] coordination are preferentially obtained from those in which ' is a protecting group for a nitrogen atom.

The compound represented by the general formula [■], which is the raw material compound of the present invention, can be produced by various methods. For example, it can be produced by the method shown in Reference Example 9 below or the method shown below. be able to.

! (1-1) (1-t) (I-a) (1-1) (I-4) [in the formula
R/ has the same meaning as above, and R1 represents a hydrogen atom, a lower alkyl group, or a 1-hydroxy lower alkyl group with a protected hydroxyl group. R.

represents a hydrogen atom, a lower alkyl group or a Fil-hydroxy lower alkyl group. R3 represents a lower alkyl group or an aralkyl group. 6R? where X represents a halogen atom and Y represents a hydroxyl group protecting group? and H? represent the same or different lower alkyl groups, or R? and R; combine with each other to represent an alkylene chain and form a 5- to 7-membered cycloalkyl group. [Human process] The compound represented by the general formula 2 is usually prepared by various known methods for obtaining an ester from a carboxylic acid, for example in the presence of a base.
Carmenic acid 1 obtained by the method described in Publication No. 96060
It can be obtained by reacting with various alkyl halides or by dehydration reaction with lower alcohols.

Step B: The compound represented by the general formula 6 is reacted with an organometallic adduct such as compound 2t-alkylmagnesium halide 1F, arylmagnesium halide, alkyllithium or aryllithium in an inert solvent, and R1 is 1
-Hydroxy lower alkyl group can be obtained by subjecting it to a commonly used conservation reaction of a hydroxyl group.

Step C The compound represented by general formula 4 can be obtained by subjecting compound 6 to a dehydration reaction carried out with a dehydrating agent such as thionyl chloride or tosyl chloride in the presence or absence of a base.

Step D: The compound represented by the general formula 5 can be prepared using various halogenating agents used when halogenating the allylmethyl group of Compound 4 in an inert solvent, such as molecular halogen, N-
It can be obtained by reacting with halogenosuccinimide or the like.

Step E: The compound represented by the general formula (I-1) can be obtained by hydrolyzing compound 5 in the presence of a low-valent ion salt of Togane ingot such as copper or silver.

Step F The compound represented by the general formula (I-2) is a compound (
1-1) can be obtained by subjecting it to a general hydroxyl group protection reaction.

Step C The compound represented by general formula 6 is compound (I-1)
can be obtained by treating with an oxidizing agent commonly used in converting alcohol to carboxylic acid, such as chromium oxide-g acid. In this reaction, carboxylic acid 6 can be obtained directly from compound (I-1) using a single oxidizing agent, but it can also be obtained by once obtaining the aldehyde and then treating it with another oxidizing agent.

Step H: The compound represented by the general formula (1-4) is prepared by combining the compound (1-1) with the general formula R'; -CO-R:
[In the formula, R1 and R; have the same meanings as above. ] or by subjecting it to an aminoacetalization reaction with a di-lower alkyl acetal derivative thereof.

The general formula (13) of the present invention produced as described above
The compound represented by can be converted into the sweet acid intermediate (II) of a 1-methylcarbapenem derivative having excellent antibacterial activity, for example, according to the method shown below (Japanese Unexamined Patent Publication No. 58-26887).

(If-1) CM-z) [wherein,
Ft, , R' and Y have the same meaning as above. ] The hydroxyl protecting group Y1 of the compound [■-1] and, if necessary, the removal reaction of the amino group protecting group is carried out simultaneously or sequentially to obtain the compound (lI-z), and the same reaction as in the above-mentioned step G is carried out. Intermediate (It) can be obtained by oxidation reaction.

Next, the present invention will be explained in detail with reference to Examples and Examples, but the present invention is not limited by these in any way.

The meanings of the abbreviations used in the following examples and reference examples are as follows.

Z: penzyloxycarbonyl group DAM di-(p-anisyl)-methyl group Me dimethyl group Et: ethyl group Ph: phenyl group THP: tetrahydropyranyl group MOM: methoxymethyl group t-Bu: t-butyl group Examples 1 4-(1-t-Butyldimethyl7lyloxymethylethenyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-7 diflu)methyl-2-azetidinone 20tt acetonitrile 200d Stir, add 4.0 d of platinum-carbon catalyst and 4 d of water under a stream of nitrogen,
After hydrogen substitution at room temperature, hydrogenation was performed at 10°C. After removing the catalyst and washing the residue with ethyl acetate, the filtrate was concentrated to give 4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl). -1-di(1)-anisyl)methyl-2-azetidinone was obtained. This product is liquid chromatograph/rough (-(
From Lichrosorb (registered trademark) RP-18゜acetonitrile-water (85:15), flow rate 1-/min] and NMR measurements, it was found to be the 4-(1-(81-t-butyldimethylsilyloxymethylethyl)) form. A mixture of q bodies is used, and the ratio is R/S=7.7.

For this mixture, ethyl acetate-n-hexane (1:
10) from a mixed solvent of 4-(1-(FD
-t-butyldimethylsilyloxymethylethyl)-3
-(1-benzyloxycarbonyloxyethyl)-1
--/(p-anisyl)methyl-2-azetidinone only can be obtained.

mp, 78-81°.

NMRδ (GDO-6m): 0.01 (6H, s)
, 0.87 (9H, s), 1.40 (3H, d,
J=6Hz), 3-51 (IH, dd, 2.2
and 7.0Hz), 6.44 (2H, d, J=5.5
Hz), 5.73 (3H, s), 3.76 (3H, s)
, 5.07 (IH, m), 5.17 (2H, s), 7.
38 (5H, s).

The reaction described in Example 1 can also proceed using the catalyst and solvent shown in the table below, and the desired product (FO form) can be obtained with priority.

Below is the margin Example 2-1 8-oxo-2,2-dimethyl-5-methylidene-7-
(1-henzyloxycargenyloxyethyl)-3-
Oxo-1-azabicyclo(4,2,0)octane 1s
Dissolve t in 180IL of ethanol and add 10% 2-)
After adding 3.6 ft of ram-carbon catalyst and stirring in a hydrogen atmosphere under water cooling for 1 hour, the catalyst was filtered off, washed with ethanol, and the rinse solution was concentrated to obtain oily 8-okino-2,2-dimethyl- 5-methyl-7-(1-hydroxyethyl)-3-
Oxo-1-azabicyclo(4,2,0]octane was obtained.

The ratio of the 5(FQ) form and the 5(S) form was 5(average/5(S)) = 2.2/1 as a result of NMRllj determination.

NMRδ (CDOA, ): 5(R) methyl form: 1.11 (3H, d, J = 7.0
Hz), 1.30 (3H, d, J=6,5H2), 1.
41 (3H, s), 1.72 (3H, s), 3.04
(IH, dd, J=2.0 and 6.0H1).

5(S) methyl body: 0.91 (3H, d, J=6
．． 5Hz), 1.30 (3H, d, J=5.5Hz),
1.41 (3H, B'j, 1.72 (3H, s), 2.
81 (1)1. dd, J=1.5 and 5.
5Hz).

Example 2-2 Spiro[cyclohexane-2,2-(8-oxo-5-
Methylidene-7-(1-benzylox7carbonyloxyethyl)-6-okino-1-azabinclo(4,2,
0) octane] to spiro[cyclohexa7-2.2-(8-oxo-5-methyl-7-(1-hydroxyethyl)-6-oxo-1) in the same manner as in Example 2-1.
-azacyclo[4°2.0]octane] was obtained. As a result of NMR measurement, this product is a mixture of 50 methyl form and 5(S) methyl form, and the ratio is 5(R)15(S) = 1.7
/ It was 1.

NMRδ (cDcn3): 5-directed methyl form: 1.11 (3H, d, J = 7.2Hz
), 1.28 (3H, d, J=6.5Hz), 3.01
(IH, dd.

J=2.0 and 5.7H1).

5 (S)/chill body: 0.90 (!IH, d,
J=6.5Hz), 1.28(3H,d, J=6.5H
z), 2.77 (IH, dd.

J = 1.5 and 5.5 Hz).

Example 2-3 3-oxo-2,2-dimethyl-5-methylidene-7-
(1-Hydroxyethyl)-6-oxo-1-azapicic 0(4,2,0)octay7.5v ethanol 1d
After adding 10% palladium-carbon 7 cape to the solution and stirring under normal pressure hydrogen for 3.5 hours, the catalyst was filtered off, washed with ethanol, and the filtrate was concentrated to obtain an oily δ-oxo-2. ,2-
Dimethyl-5-methyl-7-(1-hydroxyethyl)
-3-oxo-1-azabicyclo(4,2,0)octane was obtained. This product was obtained as a mixture of 5(R1-methyl form and 5(S)-methyl form), and the ratio thereof was 5(R)15(S)=1.5/1 as a result of NMR measurement.

Similarly to the above, S obtained by hydrogenation on a platinum oxide catalyst
-oxo-2,2-dimethyl-5-methyl-7-(1-
hydroxyethyl)-6-okino-1-azabicyclo(
4,2,0) is the result of NMR measurement, 5 (R)/5
(S)=2.82.

Example 2-4 Spiro[cyclohexane-2,2-(8-oxo-5-
Methylipore 7-(1-hydroxyethyl)-3-okino 1-azabicyclo(4,2,0)octane) 10q
Platinum oxide 2~ was added to a solution of Oxo-5-methyl-7-(1-hydroxyethyl)-6-oxo-1-azabinclo(4,2,0)octane]4N
I got a 9. As a result of NMR measurement, this product is a mixture of 5(R1-methyl form and 5(S)-methyl form), and the ratio is 5(
R) 15 (S4=3.0/1.

Example 6 (1) 4-(1-ethoxycar2nylethyl)-5-(
1-benzylox7carbonyloxyethyl)-1-t
-butyldimethylsilyl-2-azetidinone 14.6
f with ethanol and phosphate buffer (0.01M, pH 5
,7) mixture (19:1) 146d,
2.92 t of 10%/#radium-carbon catalyst was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was filtered off, washed with 100% ethyl acetate, and the filtrate was washed with 500% ethyl acetate.
After diluting with water, the mixture was washed with 10% saline, dried with sodium sulfate, and the solvent was distilled off.

(2) Dissolve the obtained residue in 100% dry benzene,
After evaporating under reduced pressure and thoroughly drying, it was dissolved in 195 d of dry dimethylformamide, and 4.5 t of imidazole,
t-Butyldimethylchlorosilane 7, Of was added and stirred at room temperature for 15 hours. Diluted with 600 yd of ethyl acetate and 600 yd of ethyl ether, washed with 10% brine, dried with nitric oxide, distilled off the whitening medium under reduced pressure, and purified the residue with silica gel chromatography to obtain 4-(1-ethoxycarinyl ethyl). -6-(1-t-butyldimethylsilyloxyethyl)-1-t-butyldimethylsilyl-2-azetidinone was obtained.

IRνrnax (tls-”): 1745.14
60.1665.1620.1250.1185.83
5.772°(3) 4-(1-1xycarbonylethyl)-3-(1-t-butyldimethyl7lyloxyethyl)-1-t-1tyldimethylsilyl-2-azetidinone 4.63 t Dissolved in 6°C of dry tetrahydrofuran, 96ml of a solution of tetra-n-butylammonium fluoride P in but-2-hydrofuran (IM) was added dropwise at 20°C, and after stirring at room temperature for 45 minutes, 250ml of ethyl acetate and The mixture was diluted with 60% 10% saline and separated. The aqueous layer was re-extracted with 50 d of ethyl acetate, and the oil layers were combined, washed with 10% brine, dried with nitric oxide, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 4-<1-ethoxycarbinylethyl)-3-(1-t-butyldimethylsilyloxyethyl)-2-azetidinone. This product is liquid chromatography (LiChrO8Orl) (registered W
mark a) 5I-60, n-hexane-isopropyl alcohol (19:1), flow rate 117 minutes
-direction-4)
)-ethoxycar2nylethyl) form is R/S=3.
It was a mixture of 7. Add this mixture to n-hexane
By repeating the recrystallization several times until R/5=10.3
/S ratio could be increased.

IRy snow? (-one: 3250.1750.1465
．． 1378.1100.865.775゜NM)1δ(cDax,): 0 body: 0.08(6H,s), 0.88(91(,s
), 1.17(3H,d, 3 =6H illusion, 1.23(
3H, d, J=7Hz), 1.28 (3)1. t,
J=7Hz), 2.97 (IH, dd, J=2.2o and 4Hz), 3.88 (IH, dd, J=2.2>
(5Hz), 4.17 (2H, Q, J=7Hz)
.

(87 bodies: 0.08 (6H, s), 0.88
(9H,S), 1.23 (3)(.

d, J=(5Hz), 1.24 (3H, d, J=
7Hz), 1.28 (3H, t, J=7Hz), 2.
76 (IH, m), 6.69 (IH, dd, J=,=
2.2 and 10H illusion, 4.16(2) 1゜q, J=7
Hz).

Example 4-1 (1) 4-(1-tetrahydrobilanyloxymethylethynyl)-5-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 25q and acetonitrile 2 .5*t bath liquid t-
The mixture was cooled to 0-5°C, 2.511 P of platinum oxide was added, and the mixture was stirred under hydrogen at normal pressure for 4 hours. It was diluted with 70 tILl of ethyl acetate, washed successively with 2N hydrochloric acid, 3d1 brine (2 times), and dried over magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure to give a white syrup of 4-(1-tetrahydropyranyloxy/methylethyl)-5-(1-benzyloxycarbonyloxyethyl>-i-c(p-anisyl)). Methyl-2-azetidinone 11q was obtained.

NMR δ (C: DC43) Near, 37 (s, 5H), 7.29 (m, 4H1,7,1
5 (m, 4H), 5.59 (s, IH), 5.16
(S, 2H), 5.11 (m, IH), 4.48
(m, 0.58), 4.67 (m, 0.5H), 3
．． 75 (m, IH), 3.75 (s, 3H), 3.
72 (s, 3H), 3.55 (d, IH), 3.
54 (d, IH), 3.15 (m, IH), 1
．． 86 (m, 11 (), 1.40 (d, 3H, J
=6.16), 0.92 (d, 5/2H, J=7.
04), 0.89(d, 3/2H.

J=6.59).

+214-(1-tetrahydropyranyloxymethylethyl)-5-(1-benzyloxycarbonyloxyethyl)-1--/-(p-anisyl)methyl-2-azetidinone 111IIP and methanol 2°0*t bath The solution was stirred at room temperature and added with 6N salt for $20.2. t/ was added and stirred for 1 hour. After neutralizing with double-blind water, the mixture was diluted with 60% of ethyl acetate, extracted, separated, washed with 2 portions of brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a colorless syrup. This was separated and purified by thin layer chromatography (silica gel; benzene: rvy, yethyl = 1:1), and 4-(1-hyroxymethylethyl) -! 1
-(1-penzyloxycarbonyloxyethyl) -
1-di(p-anisyl)methyl-2-azetidinone 7
I got vq. This product was obtained as a mixture of 5(FO-methyl form and 5(s;-methyl form), and the ratio thereof was 5(8/5 (S)) = 5.0/1 as a result of NMR measurement.

IRy max (cm-ri: 3450.1745.
1615.1515.1460.1685.1260.
1180.1035°NMFtδ (ODCJI, ): 5(S) body: 0.73 (3H, d, J-=5.8H
z), 1.41 (3H.

d, J=6.4H2), 2.93(IH, dd, J=2
．． 2 6Hz), 3.73 (!IH,s), 5
．． 75 (3H, 8), 5.11 (2H, S), 5.55
(IH, s), 7.37 (5H, s).

50 bodies: 0.89 (3H, d, J = 6.8Hz),
1.41 <3H.

d, J-=6.4Hz), 3.17(IH, dd, J=
2,2 sp and 7.5Hz), 3.73 (3H,s
), 3.75 (3H, s), 5.16 (2H, s), 5
．． 60 (IH, S), 7.37 (5H, S).

Example 4-2 (1) 4-(1-tetrahydrobylanyloxymethylethynyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 2011q and ethanol 2 Platinum monoxide 5 in a solution of .0*t and phosphate buffer (pH 6,86) 0.2-
IIIP was added, and the mixture was stirred at room temperature for 2.5 hours under normal pressure of hydrogen. The catalyst was filtered off, the solvent was distilled off under reduced pressure, diluted with 80 d of ethyl acetate, washed with 5 yd and 1 yxl of brine, and dried over magnesium sulfate.

After filtration, the solvent was distilled off under reduced pressure to obtain 4-
(1-tetrahydropyranyloxy/methylethyl)-3
-(1-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 13q was obtained.

(214-(1-f trahydropinyloxymethylethyl)-3-(1-hydroxyethyl)-1-di(p
A solution of 13q of -anisyl)methyl-2-azetidinone and 1.0 of methanol was stirred at 0-5°C, and 6N hydrochloric acid 0.
Add 11E/ and stir at room temperature for 30 minutes. After cooling, x'v
After neutralization with water, methanol was distilled off under reduced pressure, diluted with 50 d of ethyl acetate, extracted and separated, washed with brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain colorless syrup 16wIf. This was separated and purified by thin layer chromatography (silica gel; rnrR ethyl), and 4-(1-hydroxymethylethyl)-3-(1
-hydroxyethyl)-1-1-(p-anisyl)methyl-2-azetidinone 12 capes were obtained. This product is 5 (F9-
Obtained as a mixture of methyl form and 5(S)-methyl form,
The ratio i; mNMR measurement result, 5 (average/5 (S)
=2.5/1.

NMR δ (apex,) near, 71-7.16.6.90.6.81 (m, 8H)
,5.65AS)%5.55(81,(δ5.65,
5.55 total IH), 4.02 (m, IH), 3.86
(m, 1) 1), 5.80 (S, 6) 1), 3.4
9 (m, 2H), 3.09 (dd, IH), 1.8
4 (m, IH), 1.38 (d, J=6.15), 1
．． 31 (d, J=6.15) (δ1.68 and 1.
31 total 3H), 0.93 (d, J=7.84), 0.
78 (d, J=6.81) (δ0.96 and 0
．． 78 total 6H).

In the above method, when platinum oxide is hydrogenated using 10%/R radium-carbon, 5(R1
The ratio of the 513) body to the 513) body was R/S=1.6/1.

Example 5 (114-(1-Cyphenylmethylsilyloxymethylethenyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 49q and acetonitrile 4.91111 The solution was cooled to Cl-5°C, 4.9 caps of platinum oxide was added, and the mixture was stirred for 1.5 hours under normal pressure of hydrogen.The catalyst was removed, and the solvent was distilled off under reduced pressure to give a colorless syrup. 4-(1-diphenylmethylsilyloxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 44iy was obtained.

NMR δ (cacn,) Near, 59-7.41 (m, 10H), 7.35 (s
, 5H), 7.11 (da, 4H, J=2.42
, 8.79Hz), 6.73(d-d.

4H, J=2, 63, 8, 79Hz), 5.44
(S, IH), 5.12 (d, 2H, J=1.32),
5.10 (m, IH), 4.16-3.90 (m,
IH), 3.7!1 (8 to 3.71 (S), 3.69
+8) (δ3.73.3.71, 3.69 total 6H
), 5.52 (d, 2H, J=5.50), 5.
26-3.18 (m, IH), 1.60 (m, IH)
, 1.34 (d, 3H, J=6.38), 0.86 (d
, J=6.82), 0.71(d, J=6.82)(
δ0.86, 0.71 total 3H), 0.66 (Sk skin 5
8 (8) (δ0.66, 0.58 total 3H) (2) 4-(1-diphenylmethylsilyloxymethylethyl) -3-(1-benzyloxycarbonyloxyethyl) -1-di(p-7 A bath solution of 311 P of methyl-2-azetidinone and 3.1 of methanol was stirred at a low temperature of 5° C., 0.31 of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. After neutralizing with aqueous sodium bicarbonate, methanol was distilled off under reduced pressure, diluted with 80% of ethyl acetate, extracted and separated, washed with 2 d of brine, and dried over magnesium sulfate. l/
After one filtration, the solvent was distilled off under reduced pressure to obtain a colorless syrup.

This was analyzed using thin layer chromatography (silica gel; benzene:
Separation and purification with ethyl acetate = 11) gave 4-(1-(R)-
hydroxymethylethyl)-5-(1-benzyloxycarbonyloxyethyl)-1--,'-(p-anisyl)methyl-2-azetidinone 10 capes,! -4-(1-
(SJ-hydroxymethylethyl)-3-(1-t-ndyloxycargenyloxyethyl)-1-di(p-
anisyl)methyl-2-azetidinone 2q and 4-(1-
Hydroxymethylethynyl)-3-(1-benzylox7carbonyloxyethyl)-1-di(1)-anisyl)methyl-2-azetidinone 3jIF was obtained.

The two types of 4-(1-hydroxy7methylethyl) bodies obtained above are the one obtained in Example 4-1 and the IR and NM
The R spectra matched. In addition, it was confirmed in a blending test that the ethynyl compound was the same as that obtained in Reference Example 1-6 described later.

Example 6 4-(1-hydroxymethylethynyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p
-anisyl) methyl-2-azena dinone 50v and acetonitrile 5.0g was cooled to 0-5°C, 5q of platinum oxide was added, and stirred for 3 hours under normal pressure hydrogen to remove the catalyst,
The solvent was distilled off under reduced pressure to obtain colorless syrup 48-v.

This was separated and purified using thin pigeon chromatography (silica gel; benzene: ethyl acetate = 1:1), and a colorless syrup-like 4-(1
-hydroxy7methylethyl)-5-(1-benzylox7carbonylox7ethyl)-1-di(p-anisyl)methyl-2-azetidinone 46 ml was obtained. This product is 5
It was obtained as a mixture of -(R)-methyl form and 5-(S)-methyl form, and as a result of NMR measurement, the ratio was 5 (FQ15
T83=1.4/1.

Example 7 (114-(1-ethoxycarbonylethyl)-3-(
1-benzyloxycarbonyloxyethyl)-2-azetidinone 40. Dissolve Of in ethanol 600-
10% palladium-carbon at 20.0°C was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere.

The catalyst was filtered off, the solvent was distilled off under reduced pressure, and a yellow liquid (i.e.
D4-(1-ethoxycarbonylethyl)-3-(1
-Hydroxyethyl)-2-azetidinone 24.2f was obtained (yield 97%).

NMRδ (GDGJIl, ); 6.71 (br, IH), 4.17 (q, 2H, J
=7.04Hz), 4.14(m, IH), 3.78
(dd, IH, J=2.19°8.58Hz), 2
．． 98 (dd, J=1.98, 6.38Hz), 2.
88 (dd, J=1.98, 5.71Hz) (62
, 98 and 2.88 total IH), 2.60 (m, IH)
, 1.29 (t, 3H.

J=7.04Hz), 1.28 (d, 3H, J=6
．． 81Hz), 1.20 (d, 3H, J=7.04
Hz).

(2) 4-(1-ethoxycarbonylethyl)-3-(
1-Hydroxyethyl)-2-azetidinone 24.2f
and anhydrous DMF 484id under nitrogen atmosphere.
Stir at 23.degree. Of and 37.2 t of t-butyldimethylchlorosilane were added, and the mixture was stirred at room temperature for 14 hours. Diluted with 1.5 ml of ethyl acetate and diluted with 200 ml of saline.
4 and dried on a sulfuric acid magnetic column. After filtration, the solvent was distilled off under reduced pressure to obtain white yellow crystals.
The obtained 7f was separated and purified using a silica gel column Chromadog 2F (benzene-ethyl acetate) to give 4-(1-ethoxycarbonylethyl)-3-( as white crystals.
33.2 f (yield: 90 units) of 1-t-tyldimethyl7lyloxyethyl)-2-azetidinone was obtained. This product is a mixture of 5 (homogeneous methyl form and 5 (S)-methyl form), and the ratio is the result of NA4R measurement, 5 (R) 15 (S).
=1/4.3-1.

Example 8 (1) A solution of 55 wq of 4-(1-tetrahydropyranyloxymethylethynyl)-5-(1-benzyloxycarbonyloxyethyl)-1-tetrahydropyranyl-2-azetidinone and 6°5 d of acetonitrile was -5℃
3.5 q of platinum oxide was added thereto, and the mixture was stirred under normal pressure hydrogen for 5 hours. After filtration, the solvent was distilled off under reduced pressure, leaving a colorless syrup and Lte4-(1-tetrahydropyranyloxymethylethyl)-3-(1-benzyloxycarloxyethyl)-1-tetrahydropyranyl. -2-azetidinone 3711F was obtained.

NMRδ (cDai,) Near, 36 (S, 5H), 5.14 (S, 2H), 5.0
5 (m, IH), 4.94 (m, IH), 4.5
3 (br, IH), 4.05-3.44 (m, 9H
k 1.66-1.26 (m, 15H), 1.09
~0.83 (m, 3H).

(214-(1-tetrahydropyranyloxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-te)lahydropi2-2-azetidinone 67 Cape at 0-5°C, trifluoric acid 1! 1! 5.7
d and Anisole 48 Misaki were added, and the mixture was stirred for 6 hours under the same conditions. After neutralizing with sodium bicarbonate solution, concentrate the solvent amount to % under reduced pressure,
The residue was diluted with 250 x J of ethyl acetate, extracted and separated, washed with 5 d of brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain white crystals. This was separated and purified using thin layer Chromadog 2F (7 liquefied gel; benzene:ethyl acetate = 1:2) to produce 4-(1-hydroxymethylethyl)-3-(1-benzyloxycarl-nyloxyethyl). -1-tetrahydropyranyl-2-azetidinone@5q-4-(1-hydroxymethylethyl)
-3-(1-benzyloxycarl-nyloxyethyl)
-2-Azetidinone ■1 Misaki was obtained.90 ■ and ■ are mixtures of 950 and 5(S) forms according to NMR, ■ is R/S = 2.0, and ■ is f(/S = 2. It was 3.

IRyne"(cIIL-'): 3350.1
750.1740.1455.1682.1260.1
0! +00°NMRδ (cncn, ): 5 (uniform body: 0.95 (3H, d, J = 7.0Hz),
1.48 (5H.

d, J=6.5Hz), 5.14(IH, dd, , x
=2izaqH3>, 3.55 (IH, d, J=2Hz
), 5.15 (2H, S), 6°05 (IHs brt
s), 7-57 (5Hs s).

Example 9 +114-(1-tetrahydropyranyloxymethylethynyl)-3-(1-benzyloxycarloxyethyl)-2-azetidinone 25v and acetonitrile 2
．． The solution of 5- was cooled to 0-5°C, 2.5 q of platinum was added, and stirred for 3 hours under normal pressure of hydrogen. After filtration, the solvent was distilled off under reduced pressure to give a colorless syrupy 4-( 1-tetrahydropyranyloxymethylethyl)-3-(1-benzyloxycarloxyethyl)-2-azetidinone 23■
I got it.

NMRδ (CDCA3) Near, 56 (S, 5H), 6.37(k)r), 6.
30 (br), 6.20 (br), 6.14 (br)
(Total 1H), 5.14 (s, 2H), 5.09 (
q-d, IH, J=6.37), 4.50 (br,
IH), 3.92-2.91 (m, 7H), 2.
05-1.38 (m, 9H), 1.0Hd, J=6.3
7), 0.97 (d, J=6.37), 0.85 (d
, J=6.37), 0.83 (d, J=6.37
) [Total 3H, 1.50 bodies of 1,01 and 0.97, 0.
85 and 0.86 are 5(S) bodies].

1214-(1-tetrahydropyranyloxymethylethyl)-3-(1-benzyloxycarloxyethyl)-2-7zetidinone 23yw,! : A solution of 2,3 wcl of methanol was stirred at 0-5°C, 0.23 d of 6N hydrochloric acid was added, and the mixture was stirred at 20°C for 6 hours.

After cooling to 0-5°C, neutralize with aqueous sodium bicarbonate, distill methanol off under reduced pressure, dilute with 80% of ethyl acetate, extract, separate the layers, wash with 5d of brine, and remove 7g of magnesium sulfate. Dry on top. After filtration, the solvent was distilled off under reduced pressure to obtain a colorless syrup. This was subjected to thin layer chromatography (silica gel, ethyl acetate) to obtain a separated product nL, 4-(1-hydroxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-2-azetidinone 11q. This product is 5 (R
)-methyl form and 5(S)-methyl form, and the ratio was determined to be 5 (R1/51S) as a result of NMR measurement.
)=1/1,3.

Example 10 +1+4-[1-methoxymethoxymethylethyl)-3
-(1-hen noroxycarzenyloxyethyl)-
1-methoxymethyl-2-azetidinone 20 capes and acetonitrile 2. The solution of Od was cooled to 0-5°C, 2 qt of platinum oxide was added, and the mixture was stirred under normal pressure hydrogen for 6 hours. After filtration, dilute solution g with 70 ml of ethyl acetate, add 3 d of 2N hydrochloric acid, and 3 d of brine.
d (washed twice with water and dried over magnesium).

6I! , the solvent was distilled off under reduced pressure to give a colorless syrup of 4-(1-methoxymethoxymethylethyl)-6-(
1-benzyloxycarbonyloxyethyl)-1-methoxymethyl-2-azetidinone 22q was obtained.

NMRδ (GDCJ,) Near, 35 (S, 5H), 5.15 (s, 2H),
5.10 (q-d.

IH, J=7.03), 4.56 (S, 2H), 4. ．．
55 (S, 2H), 3.75 (m, IH), 3.3
9 (m, 2H), 5.35 (E3, 6H), 3.3
2 (d − d, J=7.70, 2.42), 3
．． 15 (d-d.

J=7.70, 2.42) (δ3.32 and 66.1
5 combined IH), 2.0 to 1.7 (m, IH), 1
．． 44 (d, 3H, J=6.67>, 1.03 (
d, J=6.82), 0.95 (d, J=7.03)
(3H in total of δ1.03 and 80.95).

+2) 4-(1-methoxymethoxymethylethyl)-3
-(1-benzyloxycarbonyloxyethyl)-1
-A solution of 22 methoxymethyl-2-azetidinone and 2.2 d of methanol was stirred at room temperature, and 22 wL of 6N hydrochloric acid was added.
1 was added and stirred for 6 days. After neutralization with aqueous sodium bicarbonate, the mixture was extracted with 60ml of ethyl acetate, washed with brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was separated and purified using thin layer Chromadog 2F (silica gel, benzene:ethyl acetate = 1:1) to give 4-(1-hydroxymethylethyl)-3-(1 -benzyloxycarbonyloxyethyl)-1-methoxymethyl-2-azetidinone 7Wq was obtained. This product was obtained as a mixture of 5 (FO-methyl form) and 5 (homogeneous methyl form), and the ratio thereof was 1.1/1 as a result of NMR measurement.

NMRδ (cDaIL,) Near, 36 (S, 5H), 5.15 (S, 2H), 5.0
8 (m, IH), 4.56 (s, 2H), 5.78 (
dd, J=6.16.2. <54), 3.65(d
-4, J=5.94, 2.64), (δ3.78 and δ6
．． 65 total IH), 3.57 (d, 2H, J=5
．． 49), 3.33(s), 3.33(S) (63,
66 and 66.66 combined 3H), 3.22 (m-I
H), 1-82 (br, 1H), 1.46 (d, 3
H, J = 6.37), 1.01 (d, J = 6.82),
0.91 (d, J=7.04) (3H in total of δ1.01 and δ skin 91).

The signal of the 5-position methyl group is 5(R) body δ1.01 and 5
It was separated into (S) body δ0.91.

4-(1-methoxymethoxymethylethynyl)-5-(
1-benzyloxycarbonyloxyethyl)-1-methoxymethyl-2-azetidinone 2(lv, ethyl acetate 2.0d and triethylamine 0.98yay bath solution)
Cool to -5℃, add 2 caps of platinum oxide, and heat under normal pressure hydrogen for 6 hours.
The mixture was stirred for an hour and treated in the same manner as above to obtain 4-(1-methoxymethoxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-methoxymethyl-2-azetidinone 15q. This is processed in the same way as above.
4-(1-hydroxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-methoxymethyl-2-azetidinone 4q was obtained. This product is for 5 directions.
It was obtained as a mixture of methyl form and 5-is)-methyl form, and the ratio was found to be 5 (FQ15) as a result of NMR measurement similar to the above.
(Sl=1.1/1.

Example 11 In the same manner as in Example 1, the compounds shown in Table 1 below were obtained.

Example 12 4-(1-henzyloxycardanyl ethenicari-3-(
1-4-ndyloxycarinyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 63IIf
was dissolved in 1.5a of methanol, 1.311P of nickel chloride was added under water cooling, stirred for 5 minutes, added 7.7tq of sodium borohydride, stirred for 15 minutes, and then stirred at room temperature for 1 hour. 50 ml of ethyl acetate was added to the reaction solution, washed with water, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica dull thin layer chromatography to give 4-(1-benzyloxycarbonylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-? (p-anisyl)methyl-2-azetidine/ was obtained. According to the NMR spectrum, this product was a mixture of 5@-isomer and 5(S)-isomer, and the ratio was 5 (koji/5 (Sl=4)).

IRν edict (Shin-1); 1745.1610.1585
．． 1510.1455.1682.1245.1175
．． 1025°NMRδ (CD CI=s): 0 bodies: 1.06 (3H, d, J=7.0Hz), 1.
38(3)1. d.

J=6.4H2), 3.35 (IH, dd, J=2
．． 3 and 6.7Hz), 3.70 (3H, +9),
3.73 (3H, s), 5.15 (2) 1. S), 5
．． 49 (IH, s), 7.36 (5) 1. s).

0 body - 1,06 (3H, d, J = 7.QHz), 1.3
4 (3H, d.

J=6.2Hz), 5.04 (IH, dd, J=2
．． 2 and 7.0Hz), 5.71 (3H,S), 3.
73 (3H, s), 5.15 (2H, S), 5.49 (
IH, 19), 7.32 (5H, S).

In the above method, when cobalt chloride is used instead of nickel chloride, the ratio of 51FO form and 5(S) form is R.
/S=2.0, when cupric chloride is used, E(/S-
2,2 was a mistake.

Example 13 4-(1-ethoxycarbonylethynyl)-3-(1
-benzyloxycarbonyloxyethyl)-2-azetidinone (1.04 F) was dissolved in 20 m of isopropyl alcohol, 1 g of water IC was added to this, and after cooling with water, 40 μ of nickel chloride was added, and after stirring for 5 minutes, 250 wq of sodium borohydride was added. The mixture was added all at once, stirred for 15 minutes, and then stirred at room temperature for 1 hour. After adding 300 IIL of ethyl acetate to the reaction solution and repeatedly washing with water, it was dried with sodium sulfate. The concentrated residue was chromatographed using silica gel chromatography to give 4-(1-ethoxycarbonylethyl)-3-(1
-benzyloxycarbonyloxyethyl) -2-azetidinone is a samurai. This product was determined by NMR and liquid chromatography (same conditions as Example 6) to show 54R) form and 5(S) form.
) and the ratio was R/S=0.25.

The results shown in Table 3 below were obtained using the same process as described above.

Shallow dish Example 14 +114-(1-ethoxycarbonylethyl)-6-(
1-benzyloxycarbonyloxyethyl)-1-t
-butyldimethylsilyl-2-azetidine/(6711
1? ) was dissolved in methanol 2d, nickel chloride 2wi was added under water cooling, and after stirring for 15 minutes, sodium borohydride 54'lIi was added. After stirring at room temperature for 2 hours, the mixture was diluted with 45 d of ethyl acetate, washed repeatedly with saturated brine, dried over sodium sulfate, and the solvent was distilled off.

(2) Dissolve the obtained residue in 1 d of tetrahydrofuran, add 0.14 ml of 1M tetra-n-butylammonium fluoride-tetrahydro 7 run solution at room temperature, stir for 10 minutes, and dilute with 10 d of ethyl acetate and 5 d of ethyl ether. After washing with water, the residue was dried over magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 4-(1-ethoxycarbonylethyl)''''6-(1-benzyloxycarbonyloxyethyl)-2-azetidinone.

As in Example 11, this product was also a mixture of 5(FO form and 5(S) form), and the ratio thereof was R/S = 6.6.

Reference example 1-1 4-calcyloxy-3-(1-hydroxyethyl)-1-
Di(p-anisyl)methyl-2-azetidinone 54t
Dissolve in 610d of methanol, then 2.9f of concentrated waxy acid.
After stirring at 65°C for 6 hours, the mixture was cooled to 40°C and neutralized with 8 liters of aqueous sodium hydroxide solution (15d).

The reaction solution was concentrated under reduced pressure, leaving a total residue of 105 M1 of 1,2-dichloroethane! I combed it and washed it with water. Water layer again 1.2-
Extracted with 105 d of dichloroethane, combined the organic layers, washed with water, dried sodium sulfate, and evaporated the solvent to give 4-methoxycarzenyl-3.
-(1-hydroxyethyl)-1-cy(p-anisyl)methyl-2-azetidinone was obtained.

m, p. 102-104°C.

For reference, 32.5 f of ijl-2 4-methoxycarzenyl-5-(1-hydroxyethyl)-1-di(p-aniflu)methyl-2-azetidinone was dissolved in 610 g of dry tetrahydrofuran and cooled on ice. Under a nitrogen stream, 1M-methylmagnesium zolomide-tetrahydro7 bath solution 6702 was added dropwise at 5°C or below, and after stirring for 1 hour, 350++ tons of 20% hydrochloric acid solution was added dropwise at 20 to 25°C, and the mixture was stirred for 1 hour. Next, ethyl acetate 110- was added for extraction. The aqueous layer was re-extracted with 1ioy of ethyl acetate, the organic layers were combined, and saturated brine was added.
It was washed with saturated sodium bicarbonate solution and water, and dried with sodium sulfate. The solvent was distilled off to give 4-(1-hydroxy-1-methylethyl)-3-(1-hydroxyethyl)-1-di(p-
Anisyl)methyl-2-azetidinone was obtained.

m, p, 154-156°C.

*Gal-6 4-(1-hydroxy-1-methylethyl)-6-(1
-Hydroquiquethyl)-1-di(p-7=zl)methyl-2-azetidinone 264t-Dry methylene chloride 20
0m/, then N-dimethylaminopyridine 16
F was added and cooled on ice. Under a nitrogen stream, the solution was added dropwise to 20 F' over 1 hour, stirred as it was for 2 hours, then stirred at room temperature for 10 hours, cooled on ice,
100 d of water with a specific salinity was added, and the mixture was stirred for 60 minutes to separate the liquids. The organic 1t1 was washed with water, saturated type 1 water, and p Japanese saline solution, and dried with sodium sulfate. The solvent was distilled off and 4-(1-hydroxy-1-methylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone was removed.

IRy "'(oa"): 3450.1750
．． 1615.1b15, 1250.1180.1030
゜NMRδ(CD(43): 1.1!+(6H,S),
1.38 (3H, d, J=6Hz), 5.70 (3H
,s), 3.75 (!IH,S), 5.10(2H,
s), 5°55 (IH, bs), 7.29 (5H, s)
.

Reference fIJ1-4 4-(1-hydroxy-1-methylethyl)-3-(1
-hensyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 301) Dissolve in 350 mJ of toluene, add pyridine iowLli,
Next, thionyl chloride9. Of was added dropwise at 20 to 60°C, and the mixture was stirred for 5 minutes.

Add 100 d of water to separate the liquid, wash the organic layer with water, dry mirabilite,
The solvent was evaporated and the residue was crystallized from cyclohexane-ethyl acetate to give 4-(1-methylethynyl)-5-(1-benzyloxycarbonyloxyethyl)-1-di(p-
Anisyl)methyl-2-azetidinone was obtained.

m4), 117-118°C.

Reference example l-5 4-(1-methylethynyl)-! 1-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (200F, 0.388
M) to ethyl acetate 6! A chlorine-carbon tetrachloride solution (3.85%, 870 t) was added dropwise to the mixture over 15 minutes at room temperature, followed by stirring for 1 hour. Next, 1B of water and 50% of a solution of 10% sodium sulfate in water were added and stirred, and then the organic layer was separated. After sequentially washing with an aqueous sodium bicarbonate solution and a saturated saline solution, drying with sodium sulfate and distilling off the solvent gave 4-(1-chloromethylethynyl)-3-(1-hensyloxycarbonyloxyethyl)-1-di(p- Anisyl)methyl-2-azetidinone was obtained. m, p, Ba~85°C.

Reference example l-6 4-(1-chloromethylethynyl)-5-(1-benzylox7carbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 201 was dissolved in dimethyl sulfoxide 160- and stirred. Shinaka water 40WL
1 of cuprous oxide, then 6.76 P of cuprous oxide, and 7.6 P of p-)luenesulfonic acid monohydrate. was added and stirred at 50 to 55°C for 2 hours. Cool to room temperature and add 1% phosphoric acid aqueous solution 90-
was added, diluted with 200 ml of ethyl acetate, and insoluble matter was filtered off on the top two plates. The insoluble matter was washed with 20 ml of ethyl acetate for 3 days, and the filtrate was separated into liquids. The aqueous layer was extracted with 200 ml of ethyl acetate, and the organic layers were combined, washed with saturated brine, and then dried with nitric oxide. It was concentrated under reduced pressure, and the residue was recrystallized from toluene-n-hexane (1:1) to give 4-(1-hydroxymethylethynyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p- anisyl)methyl-2-
Azetidinone was obtained.

m, p, 118-120°C.

three*? 1I2-1 4-(1-hydroxymethylethynyl)-3-(1-benzylox7carbonyloxyethyl)-1-di(p
-anisyl) methyl-2-azetidinone (20t) was dissolved in dimethylformamide (45d) and imidazole (5d) was dissolved. sr.
Next, 6.77 f of t-butyldimethylchlorosilane was added at room temperature, and the mixture was stirred for 2 hours. Cold water 200M
11 Next, 150 d of ethyl acetate was added to separate the layers. The aqueous layer was extracted with 150 ml of ethyl acetate, combined with the previous organic layer, washed twice with 80 ml of 5% hydrochloric acid water, and then three times with 80 ml of 5% saline solution, and then thoroughly dried. . The solvent was distilled off and the residue was recrystallized from isopropyl alcohol to give 4-(1-t
-butyldimethylsilyloxymethylethynyl)-5-
(1-benzyloxycarbonyloxyethyl)-1-
Di(p-anisyl)methyl-2-azetidinone was obtained.

m, p, 90-92°C.

Reference Example 2-2 4-(1-hydroxymethylethynyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p
A solution of 106q of -anisyl)methyl-2-azetidinone and i, owtl of dichloromethane was stirred at room temperature, 25 capes of dihydropyran and 1Hi of p-)luenesulfonic acid were added, and the mixture was stirred for 50 minutes. It was diluted with 100 d of ethyl acetate, washed five times with brine 2 and dried over magnesium sulfate.

After filtration, the solvent was distilled off under reduced pressure to obtain a yellow syrup of 133N.
I got i. This was carried out using thin layer chromatography (silica gel;
Separation and purification with benzene: ethyl acetate = 4: 1),
Colorless syrup 4-(1-nato-2hydropyranyloxymethylethynyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 90wl9 (yield 76%) ) attended.

NMRδ (apei,) near, 39 (s, 5H), 7.13 (m, 4H),
6.77 (m, 4H), 5.53 (s, IH)
, 5.18 (s, 2H), 5.03 (m, IH), 4.
47 (br, 0.5H), 4.25 (t, 0.5H
), 4.11 (d.

0.5H), 3.99 (d, 0.5H), 3.79 (1
)r, 2H),! 1.72 (8,3H), 3.72 (s
, 3H), 3.49 (d-d.

0.5H), 3.45 (dd, 0.5H), 1
．． 58 (br, 8H), 1.39 (d, 3H, J=
6.16).

Reference Example 2-3 4-(1-hydroxymethylethynyl)-3-(1-benzylox7carbonyloxyethyl)-1-di(p
-anisyl)methyl-2-azetidinone 106■ and anhydrous DMF 1. Stir the bath solution of Od to t-0-5℃, add imidazole 27q and diphenylmethylchlorosilane 7011.
ft- and stirred at room temperature for 10 hours. ethyl acetate 25
After diluting to 0d and washing with water, it was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a yellow syrup. This was separated and purified by thin-layer chromatography (silica gel; benzene:ethyl acetate = 4:1) to obtain a colorless liquid of 4-(1-diphenylmethylsilyloxymethylethynyl)-3-(1-be/zyloxycarg-ruoxyethyl). )-1-di<p-anisyl)methyl-2-azetidinone 98M9 and the raw material Azetidinone 62 Misaki.

NMRδ (cDaIt3) Near, 59-7.5 (m, 10H), 7.35 (S,
5H), 7.12 (dd, 4H, J=1.65.8
．． 36Hz), 6.71 (d-d.

4H, J=1.97.8.79), 5.59 (S,
IH), 5.24 (br, IH), 5.12 (d, 2
H, J = 1.09), 5.10 (m.

1H), 5.08 (br, 1H), 4.15 (d,
1)1. J=2.19), 4.00 (br, 2l
-1),! 1.70 (S, 3H), 3.67 (S,
3H), 3.16 (dd, IH, J=2.41.5.
49), 1.29 (d.

6H, J=6.38), 0.66 (s), sail 57 (S
) (δ0.66 and δ skin 57 if 3H).

Reference Example 6-1 Oxalyl chloride 8.5d was converted to methylene chloride 212
m1 and cooled to below -50°C. Next, 14.5 m of dry dimethyl sulfoxide and 42.5 m of dry methylene chloride.
Add the u-bath solution dropwise at below 50°C, stir for 10 minutes, and then add 4-(1-hydroxymethylethynyl)-3-(1-
benzyloxycarbonyloxyethyl)-1-di(
p-anisyl)methyl-2-azetidinone (45 t1) and dry methylene chloride (400 xl) were added dropwise over 15 minutes, followed by further stirring for 15 minutes.

Triethylamine 64d was added dropwise at -50°C or below, and the temperature was gradually raised to room temperature. Diluted with 480 d of cold water, made acidic by adding 6 N-salt (!
00d three times, washed with 200d of 2% sodium bicarbonate solution, washed again with 200d of saturated saline, dried and distilled off the 4-(1-
Formylethynyl)-5-(1-penzyloxycarbonyloxy7ethyl)-1-di(p-anisyl)methyl-2-azetidinone was obtained.

IRyne” (cm-”): 1760.169
5.1620.1520.1255.1185.103
0°NMRδ (cna13): 1.29 (3H, d, J
= 6.5Hz), 3.09 (IH, dd, J = 2.a oyohi 5.51 (Z), 3.61 (6H, S), 4.55
(IH, bs), 5.11 (2H, S), 5.57 (I
H,s), 5-76(IH,s), 6.03(IH,s
), -7,29 (5H,S), 9.22 (IH,s).

Reference Example 5-2 4-(1-formylethynyl)-5-(1-penzyloxycarzenyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone 4.5 f tl-t-
Dissolved in butanol 680-2-methyl-2-buty74
After adding 2.5 mg, sodium chlorite 7.15
F and 7.15 F of sodium phosphate were dissolved in 72.3 d of water and added dropwise at room temperature. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure at below 40°C. To the concentrated solution, 150 rJ of ethyl acetate and 75 d of water were added to separate the layers, the aqueous layer was re-extracted with 80 ml of ethyl acetate, and the organic layers were combined and washed with 150 d of saturated brine. Next, the mixture was extracted with 150% of saturated sodium bicarbonate solution, and after cooling with water, acidified with concentrated hydrochloric acid, and then extracted with ethyl acetate. Washed with saturated brine, dried mirabilite and distilled off 4-(1-carboxyethynyl)-
3-(1-penzyloxycarbonyloquinethyl)-
1-di(p-anisyl)methyl-2-azetidinone was obtained.

IRy ”” (cm-'): 1755
, 1620, 1520, 1255.1185.1
035°NMRδ(GDGJLs): 1.39(!IH,d
, J = 6,5Hz), 3.29 (IH, dd,
J = 2 and 5.5) IZ), 6.70 (6H = 8),
4-56 (IH, d, J=2Hz), 5.18 (2H.

S), 5.61 (IH, s), 5.68 (IH, s),
6.22 (IH.

S), 7.38 (5H, s).

Reference Example 3-3 4-(1-carboxyethynyl)-3-(1-penzyloxycargenyloxyethyl>-i-di(p-anisyl)methyl-2-azetidinone 6.7f was dissolved in acetone 60
-, add 9 ml of anhydrous potassium carbonate, 1.88 f1, and 1.4 t of benzyl bromide, and reflux for 2 hours. The mixture was cooled to room temperature, insoluble materials were removed by filtration on Celite, and the filtrate was concentrated. The concentrated solution was diluted with ethyl acetate and washed with water. After drying the sodium sulfate, it was distilled off to give 4-(1-henzyloxycardanylethenyl)-5-(1-henzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. Ta.

IRymsx (cm-”): 1755.1720
．． 1610.1510.1380.1250.1175
．． 1150.10!10°NMRδ(GDGJLs)
: 1.37 (3H, d, J = 6.5Hz), 3
．． 31 (IH, dd, J=2 O and 5.5H2)
, 6.67 (3i(,S), 3.70 (3H,8),
4.56 (IH, d, J=2Hz), 5.08 (2H
, 8), 5.17 (2H, s), 5.58 (2H, 8)
, 6.11 (IH, 8), 7.33 (5H, s), 7.
37 (5H, S).

Reference Example 4-1 320 t of 4-(1-chloromethylethynyl)-3-(1-(ndyloxycarbonyloxyethyl)-1-di(p-anisylmethyl)-2-azetidinone) was mixed with acetonitrile-water (9:1) Mixed liquid 6.81 Dissolve, 5
Ceric ammonium nitrate (CAN) below 70℃
A solution of 2.02ml of a 2r acetonitrile-water (9:1) mixture was added dropwise. To the reaction solution, 3.1% ethyl acetate and 5% water were added.
22 was added, extracted and separated, and the aqueous layer was diluted with ethyl acetate 1.7
The organic layers were combined, washed successively with Japanese brine, 5% aqueous sodium bicarbonate, and saturated brine, dried over sodium sulfate, and evaporated. 1.52 g of methanol was added to the residue, heated, and after cooling, the resulting crystals were filtered off, and liquid a was concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography to obtain 4-(1-chloromethylethynyl)-5-(1-hensyloxycarbonyloxyethyl)-2-azetidinone.

11(y ne"(cm-"): 1750.14
50.1680.1260.1165°NMRa (CDCIg): 1.46 (3H, d
, J=75.0Hz), 3.12 (IH, dd,
J=2.5o and 8.5Hz), 4.06(2H,s
), 4.31 (IH, d, J==2.5Hz), 5.1
6 (2H, S), 5.30 (2H, bs), 6.37 (
IH, bs), 7.56 (5H, S).

Reference Example 4-2 100f of 4-(1-chloromethylethynyl)-3-(1-hensyloxycarbonyloxyethyl)-2-azetidinone was dissolved in dimethyl sulfoxide-water (4:1) solution 1
! The mixture was stirred at 50° C. for 1.5 hours, and 107 f of cupric dispersion (57.6 tsp-)luenesulfonic acid was added thereto. Cool the reaction solution on ice and add saturated saline solution 6! , 2N-hydrochloric acid 1
Ethyl acetate 2! , ethyl ether 22 was added and stirred. The separated aqueous layer is re-extracted with 1 stone of ethyl acetate and 1 stone of ethyl ether, and the organic layers are combined with 2 parts of saturated brine. , washed with 22 parts of 5% sodium chloride solution and 2 parts of saturated saline solution, dried with sodium sulfate, and distilled off the solvent to obtain 4-(1-hydroxymethylethynyl)-
3-(1-hensyloxycarbonyloxyethyl)-
2-Azetidinone was obtained.

IRyn! ! ” (m-凰): 3300
, 1745, 1450, 1378, ax 1258.1135.905° NMR δ (CDCits): 1-43 (3H, d, J
= 6.5Hz), 3.1,1 (IH, dd, J = 2 and 8Hz), 4.09 (2H.

bs), 4.18 (IH, bd, J=2H2), 5
．． 12 (IH, m), 5-15 (2H, s), 6.57
(IH, bs), 7.36 (5H, s) Reference Example 5-1 Drying 4-(1-hydroxymethylethynyl)-3-(1-hensyloxycarbonyloxyethyl)-2-azetidinone 6.72 Dissolve in 26ml of methylene chloride, 2
．． 2-Dimethoxygulonogun 1.45F.

Next, boron trifluoride (needle) 0.141W! ! After stirring at room temperature for 1.5 hours, the mixture was washed with 15-cm of cooled saturated sodium bicarbonate solution, washed twice with 20-cm of cold water, and then dried with sodium sulfate. The solvent was distilled off, the residue was purified by silica gel chromatography, and the raw material was recovered and 8-oxo-2
, 2-dimethyl-5-methylisoy-7-(1-benzylox7carbonyloxyethyl)-6-oxa-1-azabicyclo[4°2.0]octane was obtained.

IRy"'(csL-'): 1755.145
5.1680.1355.1260.1140.104
0.910°NMRδ(CD(4g): 1.43(
! IH, S), 1.47 (3H, d.

J=6.5Hz), 1.70 (3H, S), 3.22
(1)1. dd.

J=2 and 8Hz), 5.17 (2H,s), 7.
37 (5H, B).

Reference Example 5-2 4-(1-hydroxymethylethynyl)-3-(1-hensyloxycarbonyloxyethyl)-2-azetidinone 6.11 and 1.1-dimethoxycyclohexane 6.
From 4f, spiro[cyclohexane-2,2-(8-oxo-5-methylidene-7-(1-benzyloxycarzenyloxyethyl)) was prepared in the same manner as in reference column 5-1.
-3-oxa-1-azabicyclo(4,2,0)-octane] was obtained.

Engineering Rνne! t(arsu: 1750.1425,12
50.1140, mx 1040.900°NMRδ (CDGig): 1.47 (3H, d, J
=6.0Hz), 1°74 (10H, bs), 3.21
(IH, dd, J=2 and 87), 5.16 (2H,
s), 7.56 (5B, s).

Reference example 6-1 4-(1-hyroxymethylethenyl)-6-(1-
From 2-azetidine (pen-zyloxycarbonyloquinethyl)-2-azetidine 651, 4-
(1-formylethynyl)-6-(1-benzyloxycarloxyethyl)-2-azetidine was obtained.

IRv 11efit (cm'): 3300.1
745.1690.1450.1680.1255.1
140.745.692°NMRδ(ODGjls):
1.46 (3H, d, J=6.5Hz), 3.10
(1)1. dd, J=2o and 7H2), 4.57
(1)(.

d, J=2Hzl, 5.17 (2H, ABQ, J=9H
z), 6.17 (IH, s), 6.48 (IH, s),
7.36 (5H, s), 9.60 (IH, s).

Reference Example 6-2 From 55t of (114-(1-formylethynyl)-5-(1penzyloxycarbonyloxyethyl)-2-azetidinone), in the same manner as in Reference Example 6-2!1l-(1-
Calxyethynyl)-3-(1-endyloxycarethynyl)-2-azetidinone was obtained.

(2) After dissolving the carvone #37F prepared in (1) above with methanol, it was diluted with diethyl ether, and a diethyl ether bath solution of diazomethane was added dropwise under water cooling, and after removing excess diazomethane, it was concentrated and the 4-(1 -methoxycarbonylethenip)-5-(1-benzylox7carbonyloxyethyl)-2-azetidine was obtained.

IRy "'(ar"): 3300.1750.
1660.1440.1380.1332.1260.
1145.750.695°NMRδ (CDCfis)
: 1.45 (3H, d, J=6.5Hz), 3, 1
5 (IH, dd, J=2 and 7Hz), 3.7
4(3)1°S), 4.52(IH, d, J=2Hz
), 5.17 (2H, s), 5.87 (IH, s),
6.32 (1)i, s), 6.58 (IH, bs)
, 7.36 (5H, s).

Reference Example 6-3 4-(1-ethoxycarponylethenyl) -6-(1
fi4-(1
-Carloxyethynyl)-3-(1-benzyloxycarloxyethyl)-2-azetidinone and ethyl iodide.

NMRδ(CDC1,s): 1.27(3H,t,
J=71(z), 1.45(3)i, d, J=6H
z), 3.18 (IH, dd, J=2.5 O and 7H
z), 4.20 (2H, q, J=7Hz), 4.56 (
IH, br, S), 5.17 (2H, s), 5.2
2 (IH, m), 5.86 (IH, s), 6.61 (
IH, sl, 6.53 (IH, br.

S), 7.39 (5H, s).

Reference Example 6-4 4-(1-ethoxycarzenylethenyl) -6-(1
-benzyloxycarloxyethyl)-2-azetidinone 1.00f was dried in dimethylformamide 12#
E/, triethylamine 0.8811 then t-
70.96f of butyldimethylchlorosila was added, and the mixture was stirred at room temperature for 15 hours. Add 50txt of ethyl acetate,
eA Washed with brine, dried with sodium sulfate, and distilled off the solvent. The residue was subjected to silica gel chromatography. t-Butyldimethylsilyl-2-azetidinone was obtained.

NMRδ (GDGj!s): 0.04 (3H, s)
, 0.26 (3H, 8), 0.95 (9H, S), 1
．． 30 (3H, t, J=7.25H2), 1.41
(!IH,d, J=6.5Hz), 3.25 (I
H, dd.

J=2.5 and 6.5Hz), 4.23(2H,q,
J=7.25Hz), 5.16 (2H, S), 5.16
(IH, m), 5.86 (IH, S), 6.30 (IH
, s), 7.35 (5H, S).

Reference Example 7-1 4-(1-hydroxymethylethynyl)-3-, (1
-benzyloxycarbonyloxyethyl)-2-azetidinone 12.12 f to dimethylformamide 120
d, and 22.26 t of triethylamine and 18.1 t of 1t-butyldimethylchlorosilane were added in sequence, and the same treatment as in Reference Example 2-1 gave 4-(1-t-butyldimethylsilyloxyethynyl)-3-(1 -Hendyloxycardanyloxyethyl-1-t-butyldimethylsilyl-2-azetidinone was obtained.

IRyn″t(oa-′): 1750.1462
．． 1680.1260, ax 1165.835°NMRδ (GDGj!s): 0.05 (6H, S)
, 0.07 (3H, S), 0.28 (3H, s), 0.
90 (9H, E3), 0.95 (9) 1. A9),
1.39 (3H, d, J=6.4Hz), 3.19 (
IH, (i(1°J=2.6 and 6.6Hz), 4.
08 (1H, d, J=2.6Hz), 4.14 (2H,
S), 5.14 (2H, 8), 7.65 (5H, 8).

Reference Example 7-2 A solution of 92q of 4-(1-hydroxymethylethynyl)-5-(1-baeroxycarzenyloxyethyl)-2-azetidinone in methylene chloride was stirred at room temperature,
Dihydropiraf 50k and p-toluenesulfone cR1
q was added, and the mixture was stirred for 1 hour under the same conditions. ethyl acetate 80
The solution was diluted with 6d d of water, washed successively with brine 6d12- and 1-d, and dried over magnesium sulfate. After filtration, the solvent was completely distilled off under reduced pressure to obtain 70 yellow whelks. This was analyzed by thin layer chromatography (silica gel, benzene: ethyl vinegar = 1:
1) Separate the silk and prepare 4-(1-tetrahydropinyloxymethylethynyl)-3-(1-benzyloxycarbonyloxyethyl)-1-nato-2hydropyranyl-2.
-Azetidinone @ 4-(1-tetrahydropyranylox7methylethenyl)-3-(1-benzyloxycarbonyloxyethyl)-2-azetidinone [phase]
58q was obtained.

@f) NMFt a (CDCA3) Near, 36 (S
, 5H), 5.26 (m, IH), 5.15 (
s, 2H), 5.06 (m, IH), 4.97 (
m, 2)1), 4.61 (m, 1)1), 4.3
4-5.22 (m, 9H), 1.84-1.38 (m
, 15H).

■NMRδ (cncn,) near, 36 (S, 5H), 6.18 (br, 0.5H),
6.11 (br.

0.5H), 5.21(br, 2H), 5.15(s,
2H), 5.08 (q, d, IH, J = 6.15), 4
．． 57 (br, 1) 1), 4.33-4.22 (m, 2
H), 4.02 (s, IH), 3.89 (m, 1) 1)
, 3.25 (m, IH), 3.16 (m, IH), 1.
58 (m, 6) i), 1.44 (d, 3H, J=6
．． 37).

Reference Example 7-3 4-(1-hydroxymethylethynyl)-3-(1e/
5.2 g of dimethoxymethane and 2.68 f of phosphorus pentoxide were added to a bath solution of 305 g of dioxycarbonyloxyethyl)-2-azetidinone and 5.24 g of chloroform, stirred at room temperature for 73 hours, diluted with 80 g of dichloromethane, Neutralized with double blind water. Extract and separate the liquid, and add 50% of the water to dichloromethane.
The remaining layer was washed with water and dried over magnesium sulfate.

After filtration, the solvent was distilled off under reduced pressure to obtain 427q of yellow syrup.
I got it. This was separated and purified by thin layer chromatography (7 licaglu, benzene: ethyl acetate = 4:1), and 4
-(1-methoxymethoxymethylethynyl)-3-(1
-benzyloxycarbonyloxyethyl)-1-methoxymethyl-2-azetidinone 159 capes (yield 41%)
and raw material 53q was obtained.

NMRδ (cacns) Near, 34 (S, 5) 1), 5.29 (1B, IH),
5.2!1 (S, IH), 5.15 (s, 2H),
5.10 (q, d, IH, J=6.37), 4.62
<d, IH, J=2.2), 4.58 (d, 2H, J
=1.10), 4.32((1,2H, J=5.5),
4.04 (S, 2H), 3.5 (m, IH), 3.3
3 (s, AH), 3.32 (s, 3H),
1.43 (d, 5H, J=6.37).

Reference Example 8-1 4-(1-(R)-t-butyldimethylsilyloxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(F-anisyl)methyl-2-azetidinone 20ft Commonly referred to as methylene chloride 200-, 1
．． Add 7.8 f of 6-simethoxybenzene, then add 10
At ~20°C, 23 t of trisulfide trichloride (f) tritoxide) was added dropwise, and after stirring at room temperature for 3 hours, the mixture was heated to 45°C and refluxed for 3 to 5 hours. After cooling to 15℃, 59 saline solution 200℃
Wash twice with d, then 2.5% Toso Sou 200-1 again with 5
Washed with 200 d of brine, dried with sodium sulfate, and distilled off the solvent. The residue was purified using silica gel chromatography and purified with 4-(
1-(R)-hydroxymethylethyl)-3-(j-benzyloxycarbonyloxyethyl)-2-azetidinone was obtained.

11(y""(m-"): 3350.1750
．． 1740.1455.1382.1260.1030
゜NMRδ-(CDCJLs): 0.95 (3H, d
, J = 7.0Hz), 1.48 (3H, d, J = 6.
5Hz), 3.14 (IH, dd.

, y=2 and 9Hz), 3.550H,d, J=2
Hz), 5.15 (2H, S), 6.05 (1) 1. b
r, s), 7.37 (5H, S).

Reference Example 8-2 Jones reagent prepared from 2.78 f of chromium trioxide, 4.4 tons of sulfuric acid and 8.1 tons of water was mixed with 4-(1-
(BJ-hydroxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-2-azetidinone 6.1 t of acetone (60 wJ)! It was added dropwise to the liquid at 10 to 20°C, and the mixture was stirred for 1 hour. Next, add 0.5d of isopropyl alcohol, stir for 15 minutes, and then add 135d1 of water.
122 d of ethyl acetate was added and dispersed. water layer 1-e#,
[Re-extract with ethyl 61d, combine the oil layer and add 5% brine 1
Washed twice with 00d. Next, 61 d of 5% sodium bicarbonate water was added to separate the layers, and the oil layer was extracted again with 30 d of 5% sodium bicarbonate water. The aqueous layer was washed with 60 ml of methylene chloride, acidified with 20 ml of 10% hydrochloric acid under water cooling, extracted twice with 60 ml of methylene chloride, washed with 10 liters of brine, dried with sodium sulfate, and the solvent was distilled off. -(1-@-cartoxyethyl)-5-(1
-benzyloxycarbonyloxyethyl)-2-azetidinone was obtained.

IRν""(cm-'): 5270.1740.
1460.1385, 1x 1270.750°NMRδ (CDCJLs): 1.19 (3H, d,
J=7.0Hz), 1.40(3H,d, J=6.2H
z), 2.67 (IH, m), 3.22 (IH, br
, d, J=7.5Hz), 3.84 (IH.

br, d, J=5.5Hz), 5.14 (2H, s)
, 6.57 (IH, br, s), 7.35 (5H, s)
, 7.63 (IH, br, s).

Reference Example 8-6 4- (1-(FQ -t-butyldimethylsilyloxymethylethyl)-5-(1-, benzyloxycarbonyloxyethyl) -1--/(1)-7nisyl)methyl-2 - 0.40 t of azetidinone to 40 t of methanol
10 d of 6N hydrochloric acid was added dropwise under water cooling, and the mixture was stirred for 20 minutes. 200 y of ethyl acetate.

1 (IIX saline solution 200- was added and fractionated. The oil layer was
After washing with brine and drying with sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain L,4-(
1-IR)-hydroxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-1-di(p-
Anisyl)methyl-2-azetidinone was obtained.

The NMR and IR data of this product were consistent with the (1-(ph-hydroxymethylethyl)) form obtained in Reference Example 10 of the tentative distribution.

Reference example? 1.535t (5mm
) was dissolved in 60 g of dry methylene chloride under a nitrogen stream, and α-
Add 5.64 t of ethyl phenylthioturobionic acid-trimethylsilylketene acetal, then add 1.6 t of zinc iodide at room temperature, stir at 35°C for 2 hours, dilute with 200 d of methylene chloride, and dilute with saturated monocarbonate solution. 100II
1 liter was added and the insoluble matter was removed. The organic layer was washed with saturated brine, dried with Glauber's salt, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 4-(1-phenylthio-1-ethoxycarbonylethyl)-3-(1-benzyl Carbonyloxyethyl)-2-azetidinone was obtained.

IRy ”” (cm-'): 1750.1380
．． 1255.1140.1015.750°NMR&, (CD(4,): 3.31 (%HJd
d, J=2.2 and7.5Hz), 5.45(%
H,br,d, J=8.4Hz), 5.12(2H,
S), 6.07 (%) f, br, s), 6.21 (M
H.

br, s), 7.31 (5/2H, s), 7.3! l
(5/2)i, S).

Reference Example 9-2 Alumina chloride 242 cape (2°IB mmol) was stirred under reflux in 10 sl of potassium borohydride under nitrogen for 6.5 hours to prepare aluminum borohydride. To this was added 250 iv (0.54 mmol) of 4-(1-phenylthio-1-ethoxycarbonylethyl)-3-(1-benzylox7carbonyloxyethyl)-2-azetidinone in anhydrous THF.
5ml/solution was added and stirred under reflux for 1.5F#f.

After cooling, 1N hydrochloric acid was added to decompose unreacted potassium borohydride, extracted six times with 30 d of ethyl acetate, organic layer f: neutralized with N carbon dioxide solution, washed with brine, and magnesium sulfate. Dry on top. After filtering, the solvent was distilled off to obtain 0.20 t of crude product. The epimer valley of 4-(1-phenylthio-1-hydroxymethylethyl)-3-(1-benzyloxycarbonyloxyethyl)-2-azetidinone was separated and purified by thin layer chromatography (silica gel, chloroform methanol = 5:1). 85 Capes,
■I got 57q. Total yield: 93.5%.

■H-NMi((CD(3m, , δ): 7.49
．． 7. 7(1)h, 5H), 6.56 (NH, IH)
, 4.15()15. IH, t-d, J=6.37
), 3.83 (84, IH, d, J = 2.20), 6
．． 55 (H8, 2H, ABd, J=2.85), 3.3
7 (H3, IH, dd, J=7.69, 1.76
), 1.39 (H6,3H,d, Jsaki = 6.16), 1.14 ((y-methyl * 5Ht S
).

■H-N discharge (GDGIL, , δ): 7.37 (
ph, 5H), 6.61 (NH, IH), 4.07 (H
5, IH, t-d, J=7.04°7.25), 3.6
5 (H4, IH, d, J = 1.98), 3.60 (H8
, 28, 8), 3.12 (H3, IH, dd, J=1
．． 76°7.48), 1.28(H7,3H,(1,J
Mitsu, 03), 1.16 (Or-methyle3'LS)e ゛ Reference Example 9-6 4-(1-phenylthio-1-hydroquinemethylethyl)-3-(1-benzylox7carponyloxyethyl)- A solution of the epimer of 2-azetidinone in anhydrous methylene chloride (0,8d) was stirred at room temperature, and acetate/dimethyl acetal 3ZjIP was added thereto, followed by boron trifluoride-ether complex 4η, and 1.5 Stir for hours.

After diluting with 30d of methylene chloride, add 0.4a of sodium bicarbonate solution.
u, washed with 0.4 d of brine (twice), and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.09 f of a crude product. Separation and purification by thin layer chromatography (silica gel; chloroform:methanol = 9:1) resulted in 8-oxo-2,2-dimethyl-5-methyl-
5-phenylthio-7-(1-hydroxyethyl)-3
A 5''IP (yield 5%) of the 5-position epimer of -oxo-1-azabicyclo(4,2°0)octane and 7q of the starting epimer were obtained.

■NMRδ (CDGAg) Near, 5 (m, 2H, Ph), 7.35 (m, 3H, Ph
), 4.21 (q-d, IH, J=5.8Hz), 3
．． 57 (d, IH, J = 2.19) IZ), 3.54 (
dd, IH, J=2.19, 5.8Hz), 3.41
(s, 1H), 3.39 (s, IH), 2.03
(br, IH), 1°84 (S,!IH), 1.4
1 (s, 3H), Ding, 30 (d, 3H.

J=6.57), 1.20 (s, 3H).

A solution of epimer 057q of 4-(1-phenylethyl-1-hydroquinemethylethyl)-3-(1-penzyloxyhydronyloxyethyl)-2-azetidinone in anhydrous methylene chloride (0,5d) was stirred at room temperature. , To this was added 25 caps of acetone dimethyl acetal, then 3 q of boron trifluoride-ether complex was added, and the mixture was stirred for 1.5 hours.

After diluting with 25yst of methylene chloride, 0.0% of saturated sodium bicarbonate solution was added.
25m/, washed with salt wood 3 times (2 times), bR0
Dry over magnesium. After filtration, the solvent was distilled off under reduced pressure to obtain 0.07 f of a crude product. Thin layer chromatography (silica gel; chloroform:methanol = 9 = 1)
8-oxo-2,2-dimethyl-5
-Methyl-5-phenylthio-7-(1-hydroxyethyl)-3-oxo-1-azabicyclo[4,2,03
Octane 5-position epimer 020q (yield 61%) and raw material epimer 09wo were obtained.

@NMRδ (CDCA3) Near, 4 (m, 2H, ph), 7.32 (m, 3H, I)
h), 4.06 (Q-(i, IH, J=6.16Hz
), 3.73 (d, IH, J=12.09), 3.56
(d, 1)i, J=1.54Hz), 3.43(d,
IH, J = 11.87), 3.04 (d, d, IH
, J=5.83, 1.87H2), 2.02(br, I
H), 1.62 (s.

3H), 1.31 (d, 3H, J=6.37), 1.2
6 (S, 6H).

Reference Example 9-4 5th position of g-oxo-2,2-dimethyl-5-methyl-5-phenylthio-7-(1-hydroxyethyl)-3-oxo-1-azabicyclo[4,2,0]octane A solution of 20 parts of epimer (1) in 4 volumes of anhydrous methylene chloride was stirred at 0-5 DEG C., and a solution of 11 q of metachloroperbenzoic acid in 21 parts of anhydrous methylene chloride was added thereto, followed by stirring for 1 hour under the same conditions.

It was diluted with 40 tg of methylene chloride, washed with 0.2 m of aqueous sodium bicarbonate solution and 0.2 m of a saline solution, and dried on a magnesium platter.

After filtration, the solvent was distilled off under reduced pressure to obtain a white-yellow syrup.
I got H1. This was carried out under reduced pressure (0.02 to 0.05 degrees Hg)
) 150-155' (1: Heating for 40 minutes, the obtained crude product was purified by thin layer chromatography (silica gel, vinegar ethyl), and r-oxo-2,2-dimethyl-5-methylidene was purified. -7-(1-hydroxyethyl)-
15 q of 3-okino-1-azobiccyclo(4,2,0) octane, 15 capes of the raw material epimer II, and 10 v of the sulfoxide compound of the raw material epimer 0 were obtained.

NMRδ(CD(J,): 5.10(d,IH,J=1.9&), 4.98(d,
1)1. J=1.54), 4.23 (m, 4H), 3
．． 10(dd, 1)1. J=5.58.1.87)
, 2.04(t)r, IH), 1.73(S, 3H)
, 1.46 (8,3H), 1.34 (d, 3H,J
=6.38).

Reference Example 9-5 4-(1-hydroxy-2-phenylthio-27”o
Hill) Epimer of -3-(1-benzylox7carbonyloxyethyl)-2-azetidinone ■56 Cape and anhydrous methylene chloride 11! 35ql of 1,1-dimethoxycyclohexane and then 3111l of boron trifluoride-ether complex were added to 1l of the bath solution, and the mixture was stirred at room temperature for 2 hours. methylene chloride 5
After diluting with 0d, the mixture was neutralized with saturated aqueous sodium bicarbonate, extracted, washed with water, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain crude product 651 gold. Thin layer chromatography (silica gel, chloroform: ethyl acetate = 1:1)
), and spiro[cyclohexane-2,2-(
8-oxo-5-methyl-5-phenylthio-7-(1
-Hydroxyethyl)-6-okino 1-azabiachlorol"4.2.0]-octane]45wqC yield 66%)
I got it.

IRv "j0": 3450.1755.1208.
1170.1060, m electrotype 750° Reference example 9-6 Spiro [cyclohexane-2,2-(δ-okino 5-
Methyl-5-phenylthio-7-(1-hydroxyethyl)-3-okino-1-azabicyclo(4,2,0)-
To a bath solution of octane (21.7) and anhydrous methylene chloride (3) was added 10.3 W of metachloroperbenzoic acid under ice cooling, and the mixture was stirred for 1 hour. It was diluted with 30ml of ethyl acetate, washed with saturated IL1 water, then brine, and dried over magnesium sulfate.

After filtration, the solvent was distilled off under reduced pressure to obtain syrup 20 capes. This was removed without solvent under reduced pressure (0.02 to 0.05 mmHg
), the reaction was heated at 130-150°C for 50 minutes, and the resulting crude product was separated and purified by thin layer chromatography (silica gel, ethyl acetate) to obtain spiro[cyclohexane-2,2-
('ij-oxo-5-methylidene-7-(1-hydroxyethyl)-3-oxo-1-azabicyclo[4゜2
．． 0] Octane 101111F was obtained.

NMRδ (cncn, ): 5.11 (d, IH, J = 1.32Hz), 4.
97 (d, IH, J = 1.32) 1z), 4.30
~4.21 (m, 4)1), 3.10 (dd,
1)1. J=5.49.1.98H2), 1.76~
1.48 (m.

10H), 1.35 (d, 3B, J=6.38)
.

Reference Example 10 Under a nitrogen stream, 0.32 f of sodium borohydride was dissolved in 40 m of dry tetrahydrofuran, and 1.81 F of boron trifluoride etherate was added dropwise at 10 to 20°C. After stirring for 11 hours, 1.5-octadiene 1.21F
was added dropwise at 10 to 20°C, and stirring was continued for 1 hour. This is added to 4-(1-methylethynyl)-3-(1-
benzyloxy7carbonyloxyethyl)-1-di(
p-anisyl)methyl-2-azetidinone 2.63 t
Dry tetrahydrofuran (10d) #r solution of 20~2
After dropping at 5℃ for 1 hour, stirring was continued for 3 hours, water was added, and after stirring for 1 hour at 10-60℃, 5.5dt of 4% sodium hydroxide water bath solution was added, and the mixture was heated to 40-45℃. Heated. Next, add 65% hydrogen peroxide at 40-45℃.
After cooling to room temperature, add sulfite (IJum 0.
21 was added thereto, 6Nlt of toluene was added to separate the layers, the aqueous layer was extracted again with 12N of toluene, and the oil layer was washed with 20% brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica glupromatography to obtain 4-(1-18
1-hydroxymethylethyl)-3-(1-henzyloxycarzenyloxyethyl)-1-di(p-anisyl)methyl-2-azetidine y1. (1-IE (l-hydroxymethylethyl) body 0.51 corresponding to ssr
I got t.

IRy"'(aa-"): 5450.1745.
1615.1515, ax 1460.1385.1260.1180.1035°NMRδ (GDCj!,): (S) body: 0.73 (3H, d, J = 6.8Hz),
1.41 (3H, d.

J = 6.4Hz), 2.93 (IH, dd, J = 2.
2 and 6Hz), 3.73 (3H,s), 3.75
(3H,s), 5.11(2E(,s), 5.55(I
H,s), 7.37 (5H,s).

0 body', 0.89 (38,d, J=-6,8Hz
), 1.41 (3H, d.

J=6.4Hz), 3.17(1)1. dd, J==2
．． 2 and 7.5H2), 5.73 (5H, s), 3.
75 (3H, E3), 5.16 (2H, s), 5.6
0 (IH, s), 7.57 (5H, s).

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R represents a hydrogen atom or a lower alkyl group,
Alternatively, the hydroxyl group represents a protected or unprotected 1-hydroxy lower alkyl group. R′ represents a hydrogen atom or a protecting group for a nitrogen atom, and R″_1 represents a methyl group, a hydroxymethyl group, a hydroxymethyl group with a protected hydroxyl group, a lower alkoxycarbonyl group, or an aralkyloxycarbonyl group. , or R' and R''_1 represent alkylene chains bonded to each other via an oxygen atom, and together with the adjacent nitrogen atom, represent a 6-membered cyclic aminoacetal group. ] A β-lactam compound represented by the general formula There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R and R' have the same meanings as above, and R″_
2 represents a hydroxymethyl group, a hydroxymethyl group with a protected hydroxyl group, a lower alkoxycarbonyl group, or an aralkyloxycarbonyl group, or R' and R
A method for producing a β-lactam compound represented by ``_2 represents an alkylene chain bonded to each other via oxygen, and together with the adjacent nitrogen atom, represents a 6-membered cyclic aminoacetal group.''